Heterocyclic derivatives of 20-amino-methyl-5-pregnen-3-ol



EETEROCYCLHC DERIVATIVES 9F ZlF-AIVHNU- RdE'IHYL-S-PREGNEN-S-UL LeonardN. Nysted, Highland Park, Ill, assignor to G. D. Searle & Co., Chicago,ill, a corporation of Delaware No Drawing. Application Qctober 31, 1957Serial No. 693,514

a ciaims. c1. 260-239.5)

The present invention relates to certain heterocyclic derivatives ofsteroids and, more particularly, to heterocyclic derivatives of20-aminomethyl-5-pregnen-3ol which can be represented by the generalstructural formula CH CH-OEz-N X CH wherein X is a member of the classconsisting of -CH CH CH -CH CH and -CH O-(IH radicals. 2 F

The compounds of this application can be conveniently prepared by thereduction of the corresponding 3-hydroxy-S-pregnene-ZO-carboxarnidesdescribed and claimed in my copending application Serial No. 488,713,filed February 16, 1955, which will issue as United States Patent No.2,813,094 on November 12, 1957, of which the present application is acontinuation-in-part.

The compounds of this invention are valuable pharmaceutical agents. Theyhave a digitalis-like stimulant action on the heart and have ahypotensive effect. Further, they antagonize the sodium-retainingactivity of the mineralocorticoid hormone aldosterone.

These bases form salts with a variety of inorganic and strong organicacids including sulfuric, phosphoric, hydrochloric, hydrobromic,sulfamic, citric, maleic, malic, ascorbic, and related acids. They alsoform quaternary ammonium salts with a variety of organic esters ofsulfuric, hydrohalic and aromatic sulfonic acids. Among such esters aremethyl chloride and bromide, ethyl chloride, propyl chloride, butylchloride, isobutyl chloride, benzyl chloride and bromide, phenethylbromide, naphthylmethyl chloride, dimethyl sulfate, diethyl sulfate,methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin,propylene chlorohydrin, allyl bromide, methallyl bromide and crotylbromide.

The invention will appear more fully from a consideration of thefollowing illustrative examples in which quantities are given in partsby weight.

Example 1 A mixture of 25 parts ofN-(3p-acetoxy-5-pregnena-ylcarbonyl)piperidine and parts of lithium alu-$46,432 Patented Aug. 5, 1958 minum hydride in 5500 parts of anhydrousether is refluxed for 4 hours and then refluxed for an additional hourwith 250 parts of ethyl acetate. The reaction mixture is then treatedwith Water and the ether solution is separated, washed with water, driedover anhydrous calcium sulfate and filtered. A stream of anhydroushydrogen chloride is passed through the ether solution and the resultingprecipitate is collected on a filter, washed with ether andrecrystallized from methanol. The resulting hydrochloride of20u-piperidinomethyl-S-pregnen- 35-01 melts with decomposition at about270300 C.

Example 2 A mixture of 5 parts ofN(3,8-acetoxy-5-pregnen-20aylcarbonxyl)pyrrolidine and 5 parts oflithium aluminum hydride in 1100 parts of an anhydrous ether is refluxedfor 3 hours and then refluxed for an hour with 50 parts of ethylacetate. After addition of Water the mixture is extracted with ether andthe ether solution is washed with water, dried over anhydrous calciumsulfate and filtered. Dry hydrogen chloride is bubbled into the ethersolution and the resulting precipitate is collected on a filter, washedwith ether and recrystallized from methanol to yield the high meltingcrystalline hydrochloride of 20a-pyrrolidinomethyl-5-pregnen-3fi-ol. Theinfrared absorption spectrum shows maxima at about 2.7 and 6.1 microns.

Example 3 A mixture of 2 parts of N-(3,B-acetoxy-ipregnen-ZW-ylcarbonyDmorpholine and 2 parts of lithium aluminum hydride in 220parts of other is refluxed for 3 hours and then heated for an hour with20 parts of ethyl acetate. It is then poured into Water and extractedwith ether. The ether solution is Washed with water, dried overanhydrous calcium sulfate and filtered. Dry hydrogen chloride is bubbledinto the ether solution until precipitation is completed. Theprecipitate is collected on a filter, Washed with ether andrecrystallized from methanol to yield the hydrochloride of20a-morpholinomethyl-5- pregnen-BB-ol which melts at about 285295 C.with decomposition.

What is claimed is:

1. A compound of the formula wherein X is a member of the classconsisting of CH CH -CH -CH -CH and CH O-CH radicals.

2. 20a-pyrrolidinomethyl- 5-pregnen-313-01. 3.ZOa-piperidinomethy1-5-pregnen-3fi-ol. 4.20oc-morpholinomethy1-5-pregnen-3fi-ol.

References Cited in the file of this patent UNITED STATES PATENTS2,813,094 Nysted Nov. 12, 1957.

1. A COMPOUND OF THE FORMULA